Pathogenesis of Disturbed Calcium Phosphate Metabolism in Renal Failure—We Have to Rewrite the Textbooks
Authors: X Bai, D. Miao, J. Li, D. Goltzman, A.C. Karaplis
Journal: Journal of the American Society of Nephrology (2005)

In the past, nephrologists were aware of the heritable disorders of renal phosphate wasting, i.e., X-linked hypophosphatemia (XLH) and the rare autosomal dominant hypophosphatemic rickets (ADHR), as well as tumor-induced osteomalacia (1), long considered exotic and rare conditions of limited practical interest. All this has dramatically changed with the unraveling of the underlying genetics. A mutation of a protease (PHEX) was identified in XLH and in ADHR, a mutation of fibroblast growth factor 23 (FGF23) located in a sequence motif crucial for cleavage by furin proteases. The exact role of PHEX is still controversial (2) and additional molecules of unknown pathogenetic significance have been identified, i.e., the phosphaturic frizzled related protein (FRP4) and matrix extracellular phosphoglycoprotein of unknown function (3). The crucial breakthrough that got this field moving has been the cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia by Shimada et al. (4). Native as well as mutated FGF23 suppresses Na+-dependent phosphate cotransport in proximal tubules (5) and—somewhat unanticipated—also reduces the 1-α hydroxylase activity as well as circulating 1,25(OH)2D3 concentrations. Recombinant FGF23 carrying the ADHR mutation causes phosphaturia and hypophosphatemia (6), and conversely targeted ablation of the FGF23 gene causes hyperphosphatemia (7), documenting the key importance of this molecule in the maintenance of normal phosphate concentrations. For nephrologists the scene has become exciting with the observation in animals and patients with impaired renal function that the concentrations of the phosphaturic “hormone” FGF23 are elevated (8–10), although some methodological points remain to be clarified. The unresolved issue remained: Was oversecretion of FGF23 just an appropriate response to phosphate retention, or was FGF23 a primary mover in renal failure provoking the known endocrine abnormalities of hyperparathyroidism and deficiency of active vitamin D? The latter possibility is rendered increasingly more plausible by recent studies. Transgenic mice expressing FGF23 under the control of an α1(I)collagen promoter in bone had low serum-P concentrations, high urinary P excretion, and high parathyroid hormone (PTH) concentrations, while there were no differences in serum creatinine and 1,25(OH)2D3 (11). Even more suggestive are the results in a model where FGF23 was overexpressed in the liver under the influence of apolipoprotein E3 as a promoter. FGF23 carried a mutation (R176Q) which protected against enzymatic degradation. Such massive overproduction of less biodegradable FGF23 caused not only hypophosphatemia and phosphaturia, but also low 1,25(OH)2D3 and massively elevated PTH concentrations associated with severe bone lesions (rickets and osteomalacia). The observation that high FGF23 causes hyperparathyroidism in the absence of renal malfunction, either directly or indirectly via lower 1,25(OH)2D3 concentrations, is obviously tantalizing in view of the question whether high FGF23 concentrations in renal failure are just an innocent reaction to hyperphosphatemia or driving the endocrine abnormalities of PTH oversecretion and 1,25(OH)2D3 underproduction. In this context it is of great interest that long ago high PTH had been noted in patients with ADHR despite normal renal function and before any therapeutic administration of phosphate (12,13). The same was seen in XLH (14). This is a rapidly moving frontier and the nephrologist is well advised to stay tuned. It is too early in the day to draw a definite pathogenetic scheme, but it is likely that in the genesis of hyperparathyroidism of renal failure, the classical trio of low Ca, high P, and low active D will now become a quartet including FGF23 as an active player.